In Alzheimer disease (AD) and rodent models for select features of AD, there is increased expression of apolipoprotein J (apoJ). This protein is also known as clusterin and many other names reflecting multiple activities. ApoJ is secreted by astrocytes and is found with aggregated amyloid b-peptide (Ab) in AD brains. This proposal is based on recent findings that apoJ and apolipoprotein E (apoE) modify the aggregation and toxicity of synthetic Ab; that aggregated Ab modifies apoJ expression; that apoJ mRNA is regulated by hormones; and that aggregated Ab and lesion models of AD induce receptors in the LDL-family that bind apoJ and apoE. The applicants propose further studies on the interactions of Ab with apoJ and apoE expression and on the regulation of apoJ by hormones. In collaboration with Grant Krafft (Northwestern U., interacting R01), they will study Ab analogs to define sequences and structures that modify bioactivities of Ab, including the induction of LDL-receptors that may mediate Ab metabolism in the brain. Astrocyte changes during aging will also be analyzed as factors in the age-related increase of AD. These studies give further tests of two hypotheses: (1) that the cytotoxicity of amyloid depends on structural features that can be modified by interactions with apoJ and other proteins that are made by brain cells; (2) that age-related changes in astrocyte activity modify responses to lesions.